Abstract Genital mucosal infections account for a majority of the reported cases of human immunodeficiency virus (HIV) transmission worldwide. Paradoxically, the mucosal epithelial cells express low to negligible levels of the HIV receptors and the mucosal tissue microenvironment is laden with numerous soluble factors containing antiviral activity and low pH. Therefore, the outcome of HIV infection is dependent on the extent to which the virus can manipulate the mucosal tissue microenvironment. For rational designing of effective intervention strategies it is important to understand the mechanisms HIV uses to successfully invade the hostile genital mucosa. We have obtained in vitro evidence to show that HIV exposure, without the need for productive infection, induced human cervical epithelial cells to produce thymic stromal lymphopoietin (TSLP), an IL-7 like cytokine, which potently activated human myeloid DC (mDC) to cause the homeostatic expansion of autologous CD4+ T cells that served as targets for HIV infection (1, 2, 3). We also obtained in vivo evidence in rhesus macaques infected with SIV by the vaginal route showing dramatic increases in TSLP expression concurrent with enhanced SIV replication in the vaginal tissues within the first two weeks (1). These results strongly suggest that TSLP clearly links the communication between epithelial cells and the DC of the immune system at a molecular level. We hypothesize that HIV-mediated TSLP production by mucosal epithelial cells is a critical trigger for DC-mediated amplification of CD4+ T cells for HIV-infection. To test this hypothesis we propose three specific aims: (a) determine the mechanism for HIV-induced TSLP expression by epithelial cells;(b) investigate how HIV-induced TSLP from the epithelial cells promotes DC-mediated expansion of CD4+ T cells for HIV infection;(c) employ the rhesus macaque model to analyze the relation between SIV-induced TSLP expression by vaginal mucosal epithelial cells and infection of CD4+ T cells in vivo. Demonstration of TSLP as an important modulator of vaginal mucosal HIV infections may assist in designing novel therapeutic strategies against genital HIV transmission.